The mammalian enteric nervous system is of interest both in its own right and as a simple model system with characteristics unique in the PNS and which resemble the CNS. The proposed research is designed to study this system and also to follow up on the considerable amount of evidence that now supports the hypothesis that the enteric nervous system contains serotonergic neurons whose cell bodies are intrinsic to the gut itself. The distribution of the enteric serotonergic neurons will be investigated both phylogenetically, in lower vertebrates and in humans and non-human primates, and within the gut. The presence or absence of serotonergic or other identified neuronal types will be examined in congenital megacolon in humans or spotted lethal mutant mice to test factors governing axonal growth. Properties of the enteric serotonergic neurons to be examined will include proximo-distal axonal transport of serotonin (5-HT) storage units, subcellular storage mechanisms for 5-HT, trytophan and 5-HT uptake and its relation to neuronal activity, 5-HT release, self-recognition by serotonergic neurons and the mechanism by which they aggregate in culture, as well as synaptic input to serotonergic neurons, and postsynaptic 5-HT receptors. In addition we will also study other neurons of the enteric nervous system including those containing polypeptides also found in brain, adrenergic-cholinergic relationships, and the relationship of the various types of neuron to one another. The approach will be an integrated one using morphological, biochemical, and physiological methods.